Therapeutic modulation of ROCK overcomes metabolic adaptation of cancer cells to OXPHOS inhibition and drives synergistic anti-tumor activity.

Autor:	Blazanin N; Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center., Liang X; Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center., Mahmud I; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center., Kim E; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center., Martinez S; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center., Tan L; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center., Chan W; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center., Anvar NE; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center., Ha MJ; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, USA., Qudratullah M; Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center., Minelli R; TRACTION Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, USA., Peoples M; TRACTION Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, USA., Lorenzi P; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center., Hart T; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center., Lissanu Y; Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center.; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 20. Date of Electronic Publication: 2024 Sep 20.
DOI:	10.1101/2024.09.16.613317
Abstrakt:	Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer. Previously, we and others have identified that SMARCA4 -mutant lung cancers are highly dependent on oxidative phosphorylation (OXPHOS). Despite initial excitements, therapeutics targeting metabolic pathways such as OXPHOS have largely been disappointing due to rapid adaptation of cancer cells to inhibition of single metabolic enzymes or pathways, suggesting novel combination strategies to overcome adaptive responses are urgently needed. Here, we performed a functional genomics screen using CRISPR-Cas9 library targeting genes with available FDA approved therapeutics and identified ROCK1/2 as a top hit that sensitizes cancer cells to OXPHOS inhibition. We validate these results by orthogonal genetic and pharmacologic approaches by demonstrating that KD025 (Belumosudil), an FDA approved ROCK inhibitor, has highly synergistic anti-cancer activity in vitro and in vivo in combination with OXPHOS inhibition. Mechanistically, we showed that this combination induced a rapid, profound energetic stress and cell cycle arrest that was in part due to ROCK inhibition-mediated suppression of the adaptive increase in glycolysis normally seen by OXPHOS inhibition. Furthermore, we applied global phosphoproteomics and kinase-motif enrichment analysis to uncover a dynamic regulatory kinome upon combination of OXPHOS and ROCK inhibition. Importantly, we found converging phosphorylation-dependent regulatory cross-talk by AMPK and ROCK kinases on key RHO GTPase signaling/ROCK-dependent substrates such as PPP1R12A, NUMA1 and PKMYT1 that are known regulators of cell cycle progression. Taken together, our study identified ROCK kinases as critical mediators of metabolic adaptation of cancer cells to OXPHOS inhibition and provides a strong rationale for pursuing ROCK inhibitors as novel combination partners to OXPHOS inhibitors in cancer treatment. Competing Interests: Declaration of Interests Y.L. and N.B. are in the process of filing a patent application of this work.
Databáze:	MEDLINE
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